CN116284241A - Novel peptides, compositions and uses thereof - Google Patents
Novel peptides, compositions and uses thereof Download PDFInfo
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- CN116284241A CN116284241A CN202310428893.9A CN202310428893A CN116284241A CN 116284241 A CN116284241 A CN 116284241A CN 202310428893 A CN202310428893 A CN 202310428893A CN 116284241 A CN116284241 A CN 116284241A
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Abstract
The invention provides a compound of formula (I) R 1 ‑X 1 ‑X 2 ‑X 3 ‑Leu‑Tyr‑X 4 ‑X 5 ‑R 2 Or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition thereof, and their use in the preparation of a composition for anti-aging or photoaging, anti-aging repair, soothing, moisturizing.
Description
Technical Field
The invention relates to the technical field of polypeptides, in particular to a peptide capable of enhancing or repairing skin barriers, a composition containing the peptide and application thereof.
Background
Skin is the first line of defense of human body, and has the functions of protecting, feeling, regulating body temperature, metabolism, etc. In the skin protection effect, the skin barrier is a key, is used as an important skin protection line, can protect the skin from injury, resist mechanical damage, avoid damage to tissues and organs, prevent invasion of external harmful substances, resist oxidization, ultraviolet damage and the like, can prevent loss of various nutrients and moisture in a body, and plays an important role in keeping the stability of the environment in a human body.
The skin barrier is composed of the sebaceous membrane, the keratinocytes and the intercellular lipids, the keratinocytes "packing" in successive intercellular lipids to form a special "brick-wall" architecture. The stratum corneum cells contain closely packed keratin, forming a plurality of insoluble bundles of keratin fibers. Among them, keratin is the main protein of keratinocytes, and only in the case of its normal expression, it can ensure the integrity of skin barrier, thereby exerting the effect of protecting skin. Filaggrin (FLG) is an important molecule for connecting keratin fibers in the stratum corneum of human skin, and under the assistance of FLG monomers, keratin fibers are regularly gathered to form a solid physical barrier at the outermost layer of epidermis, thereby preventing loss of epidermis moisture and invasion of foreign substances. FLG is distributed in different parts of the stratum corneum and gradually degraded by enzymes during keratinocyte migration into small molecular substances required by the stratum corneum, such as natural moisturizing factors. From this, it is known that silk fibroin plays an important role in moisture retention and barrier integrity maintenance.
In addition, hyaluronic acid is also an important constituent of the skin barrier, and the content of hyaluronic acid present in the skin varies with the maturation and aging processes of human skin. Hyaluronic acid can improve skin nutrition metabolism, lock moisture on skin surface, and make skin tender and smooth; meanwhile, the skin care agent can protect cells from being affected by pathogenic bacteria, quicken recovery of skin tissues, improve the physiological characteristics of skin and has the functions of natural moisturizing and skin repairing. Along with the growth of people's age and the influence of factors such as nutrition, sunlight, environment, etc., the ability of human body to synthesize hyaluronic acid gradually falls, and the content of hyaluronic acid in the skin can gradually decrease, and when the content of hyaluronic acid in the skin is less than a certain level, the water content on skin top layer can gradually decrease, causes stratum corneum cell ageing and skin inside moisture loss, makes the ageing of human epidermis. Hyaluronic acid is also decomposed by hyaluronidase and becomes an acidic stimulus with low molecular weight, thereby causing histamine release and inducing the body to produce sensitive symptoms.
Due to environmental, diet and wrong skin care, more and more people have the situation of damaged skin barrier, so that the skin has insufficient self-defense capacity, and the skin is sensitive, aged, dry and other problems, so that research and solution of the skin problems are very important. At present, the main method for improving the skin barrier function is to adopt a humectant, including a grease sealing humectant, a hydrophilic matrix moisture absorption humectant, a hydration humectant and the like, but the problem can not be fundamentally solved by pure moisture retention. Therefore, there is a need to develop an active that can fundamentally resist aging and repair against the action mechanism of improving the skin barrier function, so as to meet the increasing demands of people for caring for the skin.
Disclosure of Invention
The invention aims at providing peptides capable of enhancing or repairing skin barriers, a composition containing the peptides, and application of the peptides in aspects of aging resistance or photoaging, anti-aging repairing, relieving, moisturizing and the like.
In view of this, the present invention provides a peptide represented by the formula (I), or a stereoisomer thereof, or a mixture of its stereoisomers, or a salt thereof,
R 1 -X 1 -X 2 -X 3 -Leu-Tyr-X 4 -X 5 -R 2 (I)
in the formula (I) of the present invention,
X 1 selected from: -Gly-, -Lys-or a bond;
X 2 selected from: -Nle-, -Val-, -Leu-, or-Ile-;
X 3 selected from: -Lys-, -Arg-or-His-;
X 4 selected from: -Gly-or a bond;
X 5 selected from: -Ser-or bond;
R 1 selected from: h or R 3 -CO-，Wherein R is 3 Selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
R 2 selected from: -NR 4 R 5 OR-OR 4 Wherein each R is 4 And R is 5 Independently of each other selected from: H. substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
alkyl refers to a saturated aliphatic linear or branched alkyl group having 1 to 24 carbon atoms (optionally having 1 to 16 carbon atoms; optionally having 1 to 14 carbon atoms; optionally having 1 to 12 carbon atoms; optionally having 1, 2, 3, 4, 5, or 6 carbon atoms); optionally selected from: methyl, ethyl, isopropyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 2-ethylhexyl, 2-methylbutyl, or 5-methylhexyl;
The alkenyl group refers to a straight or branched alkenyl group having 2 to 24 carbon atoms (optionally having 2 to 16 carbon atoms; optionally having 2 to 14 carbon atoms; optionally having 2 to 12 carbon atoms; optionally having 2, 3, 4, 5, or 6 carbon atoms); the alkenyl group has one or more carbon-carbon double bonds, optionally 1, 2 or 3 conjugated or non-conjugated carbon-carbon double bonds; the alkenyl group is bound to the remainder of the molecule by a single bond; optionally selected from: vinyl, oleyl, or linoleyl;
optionally, the substituents in the "substituted alkyl", "substituted alkenyl" are selected from C 1 -C 4 An alkyl group; a hydroxyl group; c (C) 1 -C 4 An alkoxy group; an amino group; c (C) 1 -C 4 An aminoalkyl group; c (C) 1 -C 4 A carbonyloxy group; c (C) 1 -C 4 An oxycarbonyl group; halogen (e.g., fluorine, chlorine, bromine, and iodine); cyano group; a nitro group; an azide; c (C) 1 -C 4 An alkylsulfonyl group; a mercaptan; c (C) 1 -C 4 Alkylthio; c (C) 6 -C 30 Aryloxy groups such as phenoxy; -NR b (C＝NR b )NR b R c Wherein R is b And R is c Is independently selected from: H. c (C) 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 18 Aryl, C 7 -C 17 Aralkyl groups, heterocyclic groups having three to ten members, or protecting groups for amino groups.
Alternatively, R 1 Selected from: H. acetyl, t-butyryl, hexanoyl, 2-methylhexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl or linoleoyl; r is R 4 、R 5 Independently of each other selected from: H. methyl, ethyl, hexyl, dodecyl or hexadecyl;
alternatively, R 1 Selected from H, acetyl, lauroyl, myristoyl or palmitoyl; r is R 4 Is H and R 5 Selected from: H. methyl, ethyl, hexyl, dodecyl or hexadecyl;
alternatively, R 1 Is H, acetyl or palmitoyl; r is R 2 is-OH or-NH 2 。
Alternatively, the peptide represented by formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, is selected from the following peptides (1) to (40):
(1)H-Gly-Nle-Lys-Leu-Tyr-OH；
(2)Ac-Gly-Nle-Lys-Leu-Tyr-NH 2 ；
(3)Palm-Gly-Nle-Lys-Leu-Tyr-OH；
(4)Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 ；
(5)H-Val-Lys-Leu-Tyr-Gly-Ser-OH；
(6)H-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；
(7)Ac-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；
(8)Palm-Val-Lys-Leu-Tyr-Gly-Ser-OH；
(9)Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；
(10)H-Lys-Val-Lys-Leu-Tyr-OH；
(11)H-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(12)Ac-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(13)Palm-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(14)Palm-Lys-Val-Lys-Leu-Tyr-OH；
(15)H-Gly-Nle-Arg-Leu-Tyr-OH；
(16)H-Gly-Nle-Arg-Leu-Tyr-NH 2 ；
(17)Ac-Gly-Nle-Arg-Leu-Tyr-OH；
(18)Ac-Gly-Nle-Arg-Leu-Tyr-NH 2 ；
(19)Palm-Gly-Nle-Arg-Leu-Tyr-OH；
(20)Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 ；
(21)H-Lys-Leu-Lys-Leu-Tyr-OH；
(22)Ac-Lys-Leu-Lys-Leu-Tyr-NH 2 ；
(23)Ac-Gly-Ile-Lys-Leu-Tyr-NH 2 ；
(24)H-Gly-Leu-Arg-Leu-Tyr-Ser-OH；
(25)H-Gly-Val-Lys-Leu-Tyr-NH 2 ；
(26)Palm-Gly-Val-His-Leu-Tyr-NH 2 ；
(27)Ac-Gly-Nle-Arg-Leu-Tyr-GlyOH；
(28)H-Nle-Lys-Leu-Tyr-GlyOH；
(29)Ac-Ile-Lys-Leu-Tyr-Gly-Ser-NH 2 ；
(30)H-Lys-Nle-Arg-Leu-Tyr-OH；
(31)H-Ile-Lys-Leu-Tyr-Ser-NH 2 ；
(32)Ac-Gly-Nle-Lys-Leu-Tyr-OH；
(33)Palm-Gly-Leu-Lys-Leu-Tyr-NH 2 ；
(34)H-Gly-Leu-Lys-Leu-Tyr-Gly-OH；
(35)Ac-Ile-Lys-Leu-Tyr-Gly-NH 2 ；
(36)H-Ile-Arg-Leu-Tyr-Gly-Ser-OH；
(37)H-Val-His-Leu-Tyr-Gly-NH 2 ；
(38)Ac-Val-His-Leu-Tyr-Gly-Ser-OH；
(39)Palm-Gly-Leu-Arg-Leu-Tyr-Gly-NH 2 ；
(40)H-Gly-Leu-Arg--Leu-Tyr-Ser-OH。
alternatively, the peptide represented by the formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, is selected from the group consisting of the following peptide (3), peptide (4), peptide (8), peptide (9), peptide (13), peptide (14), peptide (19) and peptide (20), specifically,
(3)Palm-Gly-Nle-Lys-Leu-Tyr-OH；
(4)Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 ；
(8)Palm-Val-Lys-Leu-Tyr-Gly-Ser-OH；
(9)Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；
(13)Palm-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(14)Palm-Lys-Val-Lys-Leu-Tyr-OH；
(19)Palm-Gly-Nle-Arg-Leu-Tyr-OH；
(20)Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 。
the peptide of formula (I) of the present invention may exist as stereoisomers or as mixtures of stereoisomers; for example, the amino acids they comprise may have the L-, D-configuration, or be racemic independently of each other. Thus, it is possible to obtain isomeric mixtures as well as racemic mixtures or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and what isomers or isomeric mixtures are present. The preferred structure of the peptides of formula (I) of the present invention is the pure isomer, i.e., enantiomer or diastereomer.
For example, when-Lys-is described herein, it is understood that-Lys-is selected from-L-Lys-, -D-Lys-, or a mixture of both, is racemic or non-racemic. The preparation methods described in this document enable one of ordinary skill in the art to obtain each stereoisomer of the peptides of the invention by selecting amino acids with the correct configuration.
The invention also includes all suitable isotopic variants of the peptides of formula (I). Isotopic variations of these peptides of the present invention are understood herein to mean those compounds: wherein within the peptides of the inventionAt least one atom is replaced with another atom of the same atomic number, but the atomic mass of the other atom is different from the atomic mass normally or mainly present in nature. Examples of isotopes that can be incorporated into the peptides of the invention are: those of hydrogen, carbon, nitrogen or oxygen, e.g. 2 H (deuterium), 3 H (tritium), 13 C、 14 C、 15 N、 17 O or 18 O. Specific isotopic variations of the peptides of the present invention (particularly those into which one or more radioisotopes have been incorporated) may be advantageous, for example, for examining the mechanism of action or distribution of active compounds in vivo; due to relatively simple producibility and detectability, especially with 3 H or 14 C isotopically labeled compounds are suitable for this purpose. In addition, due to the greater metabolic stability of the compounds, the incorporation of isotopes (e.g., deuterium) may yield particular therapeutic benefits, such as increased in vivo half-life or reduced amounts of active agent required; thus, in some cases, such modifications of the peptides of the invention may also constitute preferred embodiments of the invention. Isotopic variants of the peptides of the invention can be prepared by methods known to those skilled in the art, for example, by methods further described below and in the examples, by using the respective reagents and/or corresponding isotopic modifications of the starting materials.
The term "salt" refers to a salt that is approved for use in animals, and more specifically in humans, including metal salts of peptides of formula (I), including, but not limited to: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc, or aluminum, etc.; including salts of peptides of formula (I) with organic bases including, but not limited to: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine and the like; including salts of peptides of formula (I) with inorganic or organic acids including, but not limited to: acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoate (pamoate), gluconic acid, or the like; the inorganic acids include, but are not limited to: hydrochloric acid, sulfuric acid, boric acid or carbonic acid.
The synthesis of the peptide of formula (I) or a stereoisomer or a salt thereof according to the present invention can be carried out according to conventional methods known in the art, such as solid phase synthesis, liquid phase synthesis or a combination of solid and liquid phases, and can also be prepared by biotechnological methods aimed at producing the desired sequence, or by controlled hydrolysis of proteins of animal, fungal or plant origin.
For example, a method for obtaining a peptide of formula (I) comprises the steps of:
-coupling an amino acid having a protected N-terminus and a free C-terminus with an amino acid having a free N-terminus and a protected or solid carrier-bound C-terminus;
-elimination of the group protecting the N-terminal end;
-repeating the coupling sequence and elimination of the N-terminal protecting group until the desired peptide sequence is obtained;
-elimination of the C-terminal protecting group or cleavage from the solid support.
Preferably, the C-terminus is bound to a solid support and the method is performed on a solid phase, comprising coupling an amino acid having a protected N-terminus and a free C-terminus with an amino acid having a free N-terminus and a C-terminus bound to a polymeric support; eliminating the group protecting the N-terminus; and repeating this sequence as many times as necessary to thereby obtain a peptide of the desired length, followed by cleavage of the synthesized peptide from the original polymer carrier.
The functional groups of the side chains of these amino acids remain fully protected with temporary or permanent protecting groups throughout the synthesis and may be deprotected simultaneously or orthogonally to the process of cleaving the peptide from the polymeric carrier.
Alternatively, solid phase synthesis may be performed by a pooling strategy (convergent strategy) of coupling a dipeptide or tripeptide to a polymeric support or to a dipeptide or amino acid previously bound to a polymeric support.
The functional groups of the ends may be subsequently modified using standard conditions and methods known in the art to deprotect the N-and C-termini and/or cleave the peptide from the polymeric support in a non-defined order. The peptide of formula (I) bound to the polymeric support may be optionally modified at the N-and C-termini, or after the peptide has been cleaved from the polymeric support.
In another aspect of the present invention, there is provided a composition comprising an effective amount of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, together with at least one excipient and optionally an adjuvant.
Optionally, the adjuvant is selected from: other agents that activate S1PR2 activity, analgesics, agents that inhibit PAR-2 activity, collagen synthesis stimulators, agents that modulate PGC-1 alpha synthesis, agents that modulate PPARgamma activity, agents that increase or decrease triglyceride levels in adipocytes, agents that stimulate or retard adipocyte differentiation, lipolytic or lipolysis-stimulating agents, lipolytic agents, adipogenic agents, inhibitors of acetylcholine receptor aggregation, agents that inhibit muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloproteinase inhibitors, melanin synthesis stimulators or inhibitors, whitening or decolouring agents, pro-pigmentation agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5 alpha-reductase inhibitors, inhibitors of lysyl hydroxylase and/or prolyl hydroxylase, antioxidants, free radical scavengers and/or agents that combat atmospheric pollution active carbonyl species scavengers, anti-glycation agents, antihistamines, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioning agents, moisture retaining materials, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermohydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gelling polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating the lower eye pocket, keratolytic agents, antimicrobial agents, antifungal agents, bactericides, bacteriostats, agents capable of stimulating the synthesis of dermis or epidermis macromolecules and/or inhibiting or preventing their degradation, agents that stimulate elastin synthesis, agents that stimulate decorin synthesis, agents that stimulate laminin synthesis, an agent that stimulates defensin synthesis, an agent that stimulates chaperonin synthesis, an agent that stimulates cAMP synthesis, an agent that stimulates HSP70 synthesis, an agent that stimulates heat shock protein synthesis, an agent that stimulates hyaluronic acid synthesis, an agent that stimulates fibronectin synthesis, an agent that stimulates deacetylase synthesis, an agent that stimulates synthesis of lipids and stratum corneum components, ceramides, fatty acids, an agent that inhibits collagen degradation, an agent that inhibits elastin degradation, an agent that inhibits serine proteases, an agent that stimulates fibroblast proliferation, an agent that stimulates keratinocyte proliferation, an agent that stimulates adipocyte proliferation, an agent that stimulates melanocyte proliferation, an agent that stimulates keratinocyte differentiation, an agent that inhibits acetylcholinesterase, a skin relaxant, an agent that stimulates glycosaminoglycan synthesis, an anti-hyperkeratosis agent, an acne lytic agent, an anti-psoriasis agent, an anti-rash agent DNA repair agents, DNA protectants, stabilizers, antipruritics, agents for treating and/or caring for sensitive skin, solidifying agents, tightening agents, restructuring agents, stretch-proofing agents, agents that regulate sebum production, antiperspirant agents, agents that stimulate healing, agents that assist healing, agents that stimulate re-epithelialization, agents that assist re-epithelialization, cytokines, sedatives, anti-inflammatory agents, anesthetics, agents that act on capillary circulation and/or microcirculation, agents that stimulate angiogenesis, agents that inhibit vascular permeability, venous tension agents, agents that act on cellular metabolism, agents that act on improving dermal-epidermal junction, agents that induce hair growth, hair growth inhibition or delay agents, fragrances, chelating agents, plant extracts, essential oils, marine extracts, agents from biofermentation processes, inorganic salts, cell extracts, sunscreens, agents that act on cellular metabolism, and organic or inorganic photoprotective agents effective against A and/or B ultraviolet light, or mixtures thereof.
Optionally, the formulation of the composition is selected from: cream, oil, balm, foam, lotion, gel, wipe, slurry, ointment, mousse, powder, stick, pen, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, elixir, polysaccharide film, jelly, or gelatin.
The peptides of the invention have variable solubility in water depending on the nature of their sequences or any possible modification in the N-terminal and/or C-terminal. The peptides of the invention may thus be incorporated into the composition by aqueous solutions, and those that are insoluble in water may be dissolved in conventional solvents such as, but not limited to, ethanol, propanol, isopropanol, propylene glycol, glycerol, butylene glycol or polyethylene glycol or any combination thereof.
The effective amount of the peptides of the invention to be administered, as well as their dosage, will depend on a number of factors, including the age, the state of the user, the severity of the condition, the route and frequency of administration, and the particular nature of the peptide to be used.
By "effective amount" is meant an amount of one or more peptides of the invention that is nontoxic but sufficient to provide the desired effect. The peptides of the invention are used in the compositions of the invention in concentrations effective to achieve the desired effect; in a preferred form, between 0.00000001% and 20% by weight, preferably between 0.000001% and 15% by weight, more preferably between 0.0001% and 10% by weight, and even more preferably between 0.0001% and 5% by weight, relative to the total weight of the composition.
In another aspect of the present invention, there is provided a delivery system or a sustained release system for achieving better permeation of an active ingredient, which comprises an effective amount of the peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers, or a salt thereof, or a composition thereof.
The term "delivery system" refers to a diluent, adjuvant, excipient or carrier with which the peptides of the invention are administered, selected from the group consisting of: water, oils or surfactants, including those of petroleum origin, animal origin, vegetable origin, or synthetic origin, such as, and not limited to, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters, ether sulfates, betaines, glucosides, maltosides, fatty alcohols, nonoxynol, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin, and the like. Diluents which can be used in different delivery systems to which the peptides of the invention can be administered are known to those of ordinary skill in the art.
The term "sustained release" is used in a conventional sense to refer to a delivery system that provides a gradual release of a compound over a period of time, and preferably, but not necessarily, has a relatively constant level of release of the compound over the entire period of time.
Examples of delivery systems or slow release systems are liposomes, oleosomes, nonionic surfactant liposome vesicles, ethosomes, millimeter-capsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, lipid vesicles, micelles, millimeter-spheres, microspheres, nanospheres, lipid spheres, microemulsions, nanoemulsions, millimeter-particles, microparticles or nanoparticles.
In another aspect of the present invention, there is provided the use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition thereof, or a delivery system or a sustained release system as described above, for the preparation of a composition for anti-aging or photoaging.
In another aspect of the invention there is provided the use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition thereof, or a delivery system or a sustained release system as described above, for the preparation of a composition for anti-aging repair comprising one or more of increasing cell activity, promoting cell proliferation and migration, enhancing or repairing skin barrier.
In another aspect of the present invention, there is provided the use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition thereof, or a delivery system or a sustained release system as described above, for the preparation of a composition for relief.
In another aspect of the present invention, there is provided a use of a peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained release system, for preparing a composition for moisturizing.
In the present specification, abbreviations for amino acids follow the rules specified in the European journal of biochemistry (Eur.J. biochem.1984, 138:9-37) by the IUPAC-IUB Biochemical nomenclature Commission (IUPAC-IUB Commission of Biochemical Nomenclature).
Thus, for example, lys represents NH 2 -CH(CH 2 CH 2 CH 2 CH 2 NH 2 ) -COOH, lys-represents NH 2 -CH(CH 2 CH 2 CH 2 CH 2 NH 2 ) -CO-, -Lys represents-NH-CH (CH) 2 CH 2 CH 2 CH 2 NH 2 ) -COOH, and-Lys-represents-NH-CH (CH) 2 CH 2 CH 2 CH 2 NH 2 ) -CO-. Thus, the hyphen representing the peptide bond eliminates the OH in the 1-carboxyl group of the amino acid (represented here in conventional non-ionized form) when located to the right of the symbol, and eliminates the H in the 2-amino group of the amino acid when located to the left of the symbol; both modifications can be applied to the same symbol (see table 1).
TABLE 1 Structure of amino acid residues and their single and three letter abbreviations
The abbreviation "Palm-" is used in the present invention to denote palmitoyl; gly: glycine; nle: norleucine; lys: lysine; leu: leucine; tyr: tyrosine; val: valine; ser: serine; arg: arginine.
The invention has the following advantages and effects:
1. the peptide is obtained through artificial design, is convenient to synthesize, and is safe and non-irritating to human bodies.
2. The peptide of the invention can improve cell activity, promote cell proliferation and migration, strengthen or repair skin barrier, protect skin from external injury, and has anti-aging repair effect; also has anti-aging or photoaging effects.
3. The peptide of the invention can increase the content of hyaluronic acid, promote the expression of silk fibroin, and inhibit the activity of hyaluronidase, thereby enhancing or repairing skin barrier, and having the functions of moisturizing and relieving.
Drawings
In order to more clearly illustrate the technical solutions of the present invention, the drawings that are needed in the description of the present invention will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a peptide (4) Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 (formula C) 45 H 79 N 7 O 7 ) Mass spectrum, [ M+H ]] + The mass to charge ratio (m/z) of the excimer ion peak was 830.6035 and the mass spectrum measured molecular weight was 829.60.
FIG. 2 is a peptide (9) Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 (formula C) 47 H 82 N 8 O 9 ) Mass spectrum, [ M+H ]] + The mass to charge ratio (m/z) of the excimer ion peak was 903.6204 and the mass spectrum measured molecular weight was 902.62.
FIG. 3 is a peptide (13) Palm-Lys-Val-Lys-Leu-Tyr-NH 2 (formula C) 48 H 86 N 8 O 7 ) Mass spectrum, [ M+H ]] + The mass to charge ratio (m/z) of the excimer ion peak was 887.6615 and the mass spectrum measured molecular weight was 886.66.
FIG. 4 is a peptide (14) Palm-Lys-Val-Lys-Leu-Tyr-OH (formula C) 48 H 85 N 7 O 8 ) Mass spectrum, [ M+H ]] + The mass to charge ratio (m/z) of the excimer ion peak was 888.98 and the mass spectrum measured molecular weight was 887.98.
FIG. 5 is a peptide (20) Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 (formula C) 45 H 79 N 9 O 7 ) Mass spectrum, [ M+H ]] + The mass to charge ratio (m/z) of the excimer ion peak was 858.6092 and the mass spectrum measured molecular weight was 857.61.
FIG. 6 is a graph of the effect of test samples on HaCaT cell activity.
FIG. 7 is a graph showing the effect of test samples on the activity of photoaged cells.
FIG. 8 is a graph showing the results of cell scratch experiments.
FIG. 9 is a graph of the effect of test samples on hyaluronic acid content.
FIG. 10 is a graph of the effect of test samples on FLG expression.
FIG. 11 is a graph showing the effect of a test sample on the hyaluronidase inhibition rate.
Detailed Description
In order that the described objects, features and advantages of the invention will be readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the present invention, the abbreviations used for amino acids follow the rules specified by the IUPAC-IUB Biochemical nomenclature Commission in Eur.J.biochem. (1984) 138:9-37 and J.chem. (1989) 264:633-673.
Amide Resin: a starting resin for polypeptide synthesis (crosslinking degree 1%, substitution degree 1.72mmol/g, granularity 100-200 meshes); fmoc-Linker:4- [ (2, 4-Dimethoxyphenyl) (Fmoc-amino) methyl]Phenoxyacetic acid; wang Resin: king resin; ac (Ac) 2 O: acetic anhydride; DMF: n, N-dimethylformamide; DIPEA: diisopropylethylamine; DIC: diisopropylcarbodiimide; piperidine: piperidine; HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid; TIS: triisopropylsilane; DMAP: 4-dimethylaminopyridine; palm-OH: palmitic acid; palm-: palmitoyl; gly: glycine; nle: norleucine; lys: lysine; leu: leucine; tyr: tyrosine; val: valine; ser: serine; arg: arginine; fmoc: 9-fluorenylmethoxycarbonyl; boc: a tert-butoxycarbonyl group; tBu: a tertiary butyl group; pbf:2, 4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl.
Example 1Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 Is prepared from
1.1 preparation of Fmoc-Linker-Amide Resin
9g of Amide Resin was weighed into a solid phase synthesis reaction column, swollen with DMF, washed the Resin and the solvent was removed.
8.7g Fmoc-Linker, 2.7g HOBt were weighed into a drying flask. After being dissolved by DMF solvent, the mixture is placed in ice water bath for cooling for 10min, 3.7mL of DIC is added for activation for 10min, and water vapor is avoided.
Adding the activated Fmoc-Linker into the swelled resin, reacting for 2.5 hours, pumping out the reaction liquid, washing the resin, and pumping out the solvent.
Continuing to add Ac 2 O and DIPEA were capped for 1.5h. The resin was washed and the solvent was pumped away.
1.2 Fmoc removal
Fmoc-Linker-Amide Resin was Fmoc-removed twice with 20% piperidine/DMF for 10min each time, sampled K for detection, and developed dark blue. The resin was washed 7 times with DMF and the solvent was removed.
1.3 feeding reaction
7.7g of Fmoc-Tyr (tBu) -OH and 2.7g of HOBt were weighed into a dry flask, dissolved in DMF and sealed in a-18℃refrigerator for 30min. 3.9mL DIC was added to activate for 3min to avoid water vapor. And adding the activated amino acid into the deprotected resin for reaction for 2 hours, and pumping away the reaction solution. K detection resin is colorless and transparent, which indicates that the reaction is complete.
Deprotection of the N-terminal Fmoc group was performed and 5.9g of activated Fmoc-Leu-OH was coupled to the peptidyl resin using DMF as solvent in the presence of 2.7g HOBt and 3.9mL DIC for 2h. These resins were then washed and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid. In each coupling, 7.9g of Fmoc-Lys (Boc) -OH, 7.1g of Fmoc-Nle-OH and then 5.9g of Fmoc-Gly-OH were coupled sequentially using DMF as solvent in the presence of 2.7g of HOBt and 3.9mL of DIC; after the reaction was completed, the resin was washed and the solvent was removed.
The N-terminal Fmoc group of the peptidyl resin was deprotected and Fmoc was removed twice with 20% piperidine/DMF for 10min each time, sampling K and developing dark blue. The resin was washed 6 times with DMF and the solvent was removed.
8.6g of Palm-OH was coupled to the peptidyl Resin using DMF as solvent in the presence of 5.4g HOBt and 7.7mL DIC, the reaction was continued for 2.5h, the Resin was washed, the solvent was removed, and after shrink drying 19.4g of Palm-Gly-Nle-Lys (Boc) -Leu-Tyr (tBu) -Linker-Amide Resin was obtained.
1.4 cleavage
114mL of TFA, 3mL of TIS and 3mL of water are measured, mixed and stirred uniformly to obtain a lysate, and the lysate is sealed and placed in a refrigerator at the temperature of minus 18 ℃ for standby; the isopropyl ether is placed in a refrigerator at the temperature of minus 18 ℃ for refrigeration for standby.
19.4g of Palm-Gly-Nle-Lys (Boc) -Leu-Tyr (tBu) -Linker-Amide Resin was weighed, added to a round bottom flask, the frozen lysate was added, and the reaction was stirred for 2h. Suction filtering, collecting filtrate, concentrating to 15mL, adding isopropyl ether, stirring, centrifuging, washing for 6 times, and vacuum drying to obtain 14.0g Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 Crude peptide.
1.5 purification
14.0g of the crude peptide was weighed and dissolved in 360mL of a mixed solution of acetic acid, methanol and water, and the solution was filtered through a microporous membrane having a pore size of 0.22 μm to obtain a clear and transparent solution, which was purified by reverse phase HPLC, the purification gradient was as shown in the following Table:
Purifying the filtered sample, collecting the fraction, concentrating and freeze-drying to obtain the peptide (4) Palm-Gly-Nle-Lys-Leu-Tyr-NH with the purity of 97.16% 2 。
Example 2Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 Is prepared from
2.1 preparation of Fmoc-Linker-Amide Resin
9g of Amide Resin was weighed into a solid phase synthesis reaction column, swollen with DMF, washed the Resin and the solvent was removed.
8.7g Fmoc-Linker, 2.6g HOBt were weighed into a drying flask. After being dissolved by DMF solvent, the mixture is placed in ice water bath for cooling for 10min, 3.7mL of DIC is added for activation for 10min, and water vapor is avoided.
Adding the activated Fmoc-Linker into the swelled resin, reacting for 2.5 hours, pumping out the reaction liquid, washing the resin, and pumping out the solvent.
Continuing to add Ac 2 O and DIPEA were capped for 1.5h. The resin was washed and the solvent was pumped away.
2.2 Fmoc removal
Fmoc-Linker-Amide Resin was Fmoc-removed twice with 20% piperidine/DMF for 10min each time, sampled K for detection, and developed dark blue. The resin was washed 7 times with DMF and the solvent was removed.
2.3 feeding reaction
6.5g of Fmoc-Ser (tBu) -OH and 2.7g of HOBt were weighed into a drying flask, dissolved in DMF and sealed in a-18℃refrigerator for 30min. 3.9mL DIC was added to activate for 3min to avoid water vapor. And adding the activated amino acid into the deprotected resin for reaction for 2 hours, and pumping away the reaction solution. K detection resin is colorless and transparent, which indicates that the reaction is complete.
The N-terminal Fmoc group was deprotected and 5.0g of activated Fmoc-Gly-OH was coupled to the peptidyl resin using DMF as solvent in the presence of 2.7g HOBt and 3.7mL DIC, and the reaction was continued for 2h. These resins were then washed and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid. In each coupling, 7.7g of Fmoc-Tyr (tBu) -OH, 7.1g of Fmoc-Leu-OH, 9.4g of Fmoc-Lys (Boc) -OH and then 6.8g of Fmoc-Val-OH were coupled sequentially using DMF as solvent in the presence of 2.7g of HOBt and 3.7mL of DIC; after the reaction was completed, the resin was washed and the solvent was removed.
The N-terminal Fmoc group of the peptidyl resin was deprotected and Fmoc was removed twice with 20% piperidine/DMF for 10min each time, sampling K and developing dark blue. The resin was washed 6 times with DMF and the solvent was removed.
8.6g of Palm-OH was coupled to the peptidyl Resin using DMF as solvent in the presence of 5.4g HOBt and 7.7mL DIC, the reaction was continued for 2.5h, the Resin was washed, the solvent was removed, and after shrink drying 21.5g of Palm-Val-Lys (Boc) -Leu-Tyr (tBu) -Gly-Ser (tBu) -Linker-Amide Resin was obtained.
2.4 cleavage
114mL of TFA, 3mL of TIS and 3mL of water are measured, mixed and stirred uniformly to obtain a lysate, and the lysate is sealed and placed in a refrigerator at the temperature of minus 18 ℃ for standby; the isopropyl ether is placed in a refrigerator at the temperature of minus 18 ℃ for refrigeration for standby.
21.5g of Palm-Val-Lys (Boc) -Leu-Tyr (tBu) -Gly-Ser (tBu) -Linker-Amide Resin was weighed, added to a round bottom flask, the frozen lysate was added and the reaction was stirred for 2h. Suction filtering, collecting filtrate, concentrating to 15mL, adding isopropyl ether, stirring, centrifuging, washing for 6 times, and vacuum drying to obtain 10.3g Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 Crude peptide.
2.5 purification
10.3g of the crude peptide was weighed and dissolved in 800mL of a mixed solution of acetic acid and water, and the solution was filtered through a microporous membrane having a pore size of 0.22 μm to obtain a clear and transparent solution, which was purified by reverse phase HPLC, and the purification gradient was as shown in the following Table.
| Time (min) | Flow rate (mL/min) | A% (acetonitrile) | B% (0.1% acetic acid + pure water) |
| 0 | 40 | 10 | 90 |
| 10 | 40 | 25 | 75 |
| 20 | 40 | 50 | 50 |
| 30 | 40 | 65 | 35 |
| 60 | 40 | 65 | 35 |
Purifying the filtered sample, collecting the fraction, concentrating and freeze-drying to obtain the peptide (9) Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH with the purity of 97.08% 2 。
Example 3Palm-Lys-Val-Lys-Leu-Tyr-NH 2 Is prepared from
3.1 preparation of Fmoc-Linker-Amide Resin
9g of Amide Resin was weighed into a solid phase synthesis reaction column, swollen with DMF, washed the Resin and the solvent was removed.
8.7g Fmoc-Linker, 2.6g HOBt were weighed into a drying flask. After being dissolved by DMF solvent, the mixture is placed in ice water bath for cooling for 10min, 3.7mL of DIC is added for activation for 10min, and water vapor is avoided.
Adding the activated Fmoc-Linker into the swelled resin, reacting for 2.5 hours, pumping out the reaction liquid, washing the resin, and pumping out the solvent.
Continuing to add Ac 2 O and DIPEA were capped for 1.5h. The resin was washed and the solvent was pumped away.
3.2 Fmoc removal
Fmoc-Linker-Amide Resin was Fmoc-removed twice with 20% piperidine/DMF for 10min each time, sampled K for detection, and developed dark blue. The resin was washed 7 times with DMF and the solvent was removed.
3.3 feeding reaction
7.7g of Fmoc-Tyr (tBu) -OH and 2.7g of HOBt were weighed into a dry flask, dissolved in DMF and sealed in a-18℃refrigerator for 30min. 3.9mL DIC was added to activate for 3min to avoid water vapor. And adding the activated amino acid into the deprotected resin for reaction for 2 hours, and pumping away the reaction solution. K detection resin is colorless and transparent, which indicates that the reaction is complete.
Deprotection of the N-terminal Fmoc group was performed and 5.9g of activated Fmoc-Leu-OH was coupled to the peptidyl resin using DMF as solvent in the presence of 2.7g HOBt and 3.9mL DIC for 2h. These resins were then washed and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid. In each coupling, 7.9g of Fmoc-Lys (Boc) -OH, 6.8g of Fmoc-Val-OH and then 9.4g of Fmoc-Lys (Boc) -OH were coupled sequentially using DMF as solvent in the presence of 2.7g of HOBt and 3.9mL of DIC; after the reaction was completed, the resin was washed and the solvent was removed.
The N-terminal Fmoc group of the peptidyl resin was deprotected and Fmoc was removed twice with 20% piperidine/DMF for 10min each time, sampling K and developing dark blue. The resin was washed 6 times with DMF and the solvent was removed.
8.6g of Palm-OH was coupled to the peptidyl Resin using DMF as solvent in the presence of 5.4g HOBt and 7.7mL DIC, the reaction was continued for 2.5h, the Resin was washed, the solvent was removed, and after shrink drying 19.8g of Palm-Lys (Boc) -Val-Lys (Boc) -Leu-Tyr (tBu) -Linker-Amide Resin was obtained.
3.4 cleavage
Measuring 152mL of TFA, 4mL of TIS and 4mL of water, mixing and stirring uniformly to obtain a lysate, sealing and placing in a refrigerator at the temperature of minus 18 ℃ for later use; the isopropyl ether is placed in a refrigerator at the temperature of minus 18 ℃ for refrigeration for standby.
19.8g of Palm-Lys (Boc) -Val-Lys (Boc) -Leu-Tyr (tBu) -Linker-Amide Resin was weighed, added to a round bottom flask, the frozen lysate was added, and the reaction was stirred for 2h. Suction filtration, collecting filtrate, concentrating to 15mL, adding isopropyl ether, stirring, centrifuging and washing for 6 times, and vacuum drying to obtain 6.3g Palm-Lys-Val-Lys-Leu-Tyr-NH 2 Crude peptide.
3.5 purification
6.3g of the crude peptide was weighed and dissolved in 450mL of a mixed solution of acetic acid, methanol and water, and the solution was filtered through a microporous membrane having a pore size of 0.22 μm to obtain a clear and transparent solution, which was purified by reverse phase HPLC, the purification gradient was as shown in the following Table:
| Time (min) | Flow rate (mL/min) | A% (acetonitrile) | B% (0.1% acetic acid + pure water) |
| 0 | 40 | 10 | 90 |
| 10 | 40 | 25 | 75 |
| 20 | 40 | 35 | 65 |
| 30 | 40 | 40 | 60 |
| 50 | 40 | 50 | 50 |
| 80 | 40 | 60 | 40 |
Purifying the filtered sample, collecting the fraction, concentrating and freeze-drying to obtain peptide (13) Palm-Lys-Val-Lys-Leu-Tyr-NH with purity of 96.55% 2 。
Example 4 preparation of Palm-Lys-Val-Lys-Leu-Tyr-OH
4.1 swelling and reaction of the resin
10g of Wang Resin was weighed into a solid phase synthesis reaction column, swollen with DMF, washed the Resin and the solvent was removed.
11.0g of Fmoc-Tyr (tBu) -OH, 4.0g of HOBt were weighed into a dry flask. Dissolving with DMF solvent, cooling in ice water bath for 10min, and adding 6mL DIC for 10min to avoid water vapor.
The activated Fmoc-Tyr (tBu) -OH and 1.5g DMAP were added to the swollen resin and reacted for 2.5h, the reaction solution was removed, the resin was washed, and the solvent was removed.
Continuing to add Ac 2 O, DIPEA and DMAP capping for 1.5h. The resin was washed and the solvent was pumped away.
4.2 Fmoc removal
Fmoc-Tyr (tBu) -Wang Resin was Fmoc-removed twice with 20% piperidine/DMF for 10min each time, sampled K and developed dark blue. The resin was washed 7 times with DMF and the solvent was removed.
4.3 feeding reaction
7g of Fmoc-Leu-OH and 3g of HOBt were weighed into a dry flask, dissolved in DMF and sealed in a refrigerator at-18℃for 30min. Adding 5mL DIC to activate for 3min to avoid water vapor. And adding the activated amino acid into the deprotected resin for reaction for 2 hours, and pumping away the reaction solution. K detection resin is colorless and transparent, which indicates that the reaction is complete.
The N-terminal Fmoc group was deprotected and 9g of Fmoc-Lys (Boc) -OH after activation was coupled to the peptidyl resin using DMF as solvent in the presence of 3g HOBt and 5mL DIC for 2h. These resins were then washed and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid. In each coupling, 8g of Fmoc-Val-OH followed by 11g of Fmoc-Lys (Boc) -OH were coupled sequentially using DMF as solvent in the presence of 3g HOBt and 5mL DIC; after the reaction was completed, the resin was washed and the solvent was removed.
The N-terminal Fmoc group of the peptidyl resin was deprotected and Fmoc was removed twice with 20% piperidine/DMF for 10min each time, sampling K and developing dark blue. The resin was washed 6 times with DMF and the solvent was removed.
10g of Palm-OH was coupled to the peptidyl resin using DMF as solvent in the presence of 7g HOBt and 9mL DIC, the reaction was continued for 2.5h, the resin was washed, the solvent was removed, and after shrink drying 23g of Palm-Lys (Boc) -Val-Lys (Boc) -Leu-Tyr (tBu) -Wangresin was obtained.
4.4 cleavage
Measuring 131mL of TFA, 3.5mL of TIS and 3.5mL of water, uniformly mixing and stirring to obtain a lysate, sealing and placing in a refrigerator at-18 ℃ for later use; the isopropyl ether is placed in a refrigerator at the temperature of minus 18 ℃ for refrigeration for standby.
23g of Palm-Lys (Boc) -Val-Lys (Boc) -Leu-Tyr (tBu) -Wang Resin was weighed, added to a round bottom flask, the frozen lysate was added and the reaction was stirred for 2h. Suction filtration, collecting filtrate, concentrating to 15mL, adding isopropyl ether, stirring, centrifuging and washing for 6 times, and vacuum drying to obtain 13g Palm-Lys-Val-Lys-Leu-Tyr-OH crude peptide.
4.5 purification
13g of the crude peptide was weighed and dissolved in 220mL of a mixed solution of acetic acid, methanol and water, and filtered with a microporous membrane having a pore size of 0.22 μm to give a clear and transparent solution, which was purified by reverse phase HPLC, the purification gradient being as shown in the following Table:
| time (min) | Flow rate (mL/min) | A% (acetonitrile) | B% (0.1% acetic acid + pure water) |
| 0 | 40 | 25 | 75 |
| 15 | 40 | 35 | 65 |
| 30 | 40 | 45 | 55 |
| 45 | 40 | 60 | 40 |
| 80 | 40 | 65 | 35 |
| 100 | 40 | 65 | 35 |
And (3) purifying the filtered sample, collecting fractions, concentrating and freeze-drying to obtain the peptide (14) Palm-Lys-Val-Lys-Leu-Tyr-OH with the purity of 97.615%.
Example 5Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 Is prepared from
5.1 preparation of Fmoc-Linker-Amide Resin
9g of Amide Resin was weighed into a solid phase synthesis reaction column, swollen with DMF, washed the Resin and the solvent was removed.
8.7g Fmoc-Linker, 2.6g HOBt were weighed into a drying flask. After being dissolved by DMF solvent, the mixture is placed in ice water bath for cooling for 10min, 3.7mL of DIC is added for activation for 10min, and water vapor is avoided.
Adding the activated Fmoc-Linker into the swelled resin, reacting for 2.5 hours, pumping out the reaction liquid, washing the resin, and pumping out the solvent.
Continuing to add Ac 2 O and DIPEA were capped for 1.5h. The resin was washed and the solvent was pumped away.
5.2 Fmoc removal
Fmoc-Linker-Amide Resin was Fmoc-removed twice with 20% piperidine/DMF for 10min each time, sampled K for detection, and developed dark blue. The resin was washed 7 times with DMF and the solvent was removed.
5.3 feeding reaction
7.7g of Fmoc-Tyr (tBu) -OH and 2.7g of HOBt were weighed into a dry flask, dissolved in DMF and sealed in a-18℃refrigerator for 30min. 3.9mL DIC was added to activate for 3min to avoid water vapor. And adding the activated amino acid into the deprotected resin for reaction for 2 hours, and pumping away the reaction solution. K detection resin is colorless and transparent, which indicates that the reaction is complete.
Deprotection of the N-terminal Fmoc group was performed and 5.9g of activated Fmoc-Leu-OH was coupled to the peptidyl resin using DMF as solvent in the presence of 2.7g HOBt and 3.9mL DIC for 2h. These resins were then washed and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid. In each coupling, 15.2g of Fmoc-Arg (Pbf) -OH, 7.1g of Fmoc-Nle-OH and then 5.9g of Fmoc-Gly-OH were coupled sequentially using DMF as solvent in the presence of 2.7g of HOBt and 3.9mL of DIC; after the reaction was completed, the resin was washed and the solvent was removed.
The N-terminal Fmoc group of the peptidyl resin was deprotected and Fmoc was removed twice with 20% piperidine/DMF for 10min each time, sampling K and developing dark blue. The resin was washed 6 times with DMF and the solvent was removed.
8.6g of Palm-OH was coupled to the peptidyl Resin using DMF as solvent in the presence of 5.4g HOBt and 7.7mL DIC, the reaction was continued for 1.5h, the Resin was washed, the solvent was removed, and after shrink drying 18.2g of Palm-Gly-Nle-Arg (Pbf) -Leu-Tyr (tBu) -Linker-Amide Resin was obtained.
5.4 cleavage
Measuring 152mL of TFA, 4mL of TIS and 4mL of water, mixing and stirring uniformly to obtain a lysate, sealing and placing in a refrigerator at the temperature of minus 18 ℃ for later use; the isopropyl ether is placed in a refrigerator at the temperature of minus 18 ℃ for refrigeration for standby.
18.2g of Palm-Gly-Nle-Arg (Pbf) -Leu-Tyr (tBu) -Linker-Amide Resin was weighed, added to a round bottom flask, the frozen lysate was added, and the reaction was stirred for 2h. Suction filtering, collecting filtrate, concentrating to 15mL, adding isopropyl ether, stirring, centrifuging, washing for 6 times, and vacuum drying to obtain 13g Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 Crude peptide.
5.5 purification
13g of the crude peptide was weighed and dissolved in 220mL of a mixed solution of acetic acid and water, and filtered with a microporous membrane having a pore size of 0.22 μm to obtain a clear and transparent solution, which was purified by reverse phase HPLC, the purification gradient being as shown in the following Table:
Purifying the filtered sample, collecting the fraction, concentrating and freeze-drying to obtain the peptide (20) Palm-Gly-Nle-Arg-Leu-Tyr-NH with purity of 98.23% 2 。
Example 6
Other peptides of formula (I) of the present invention may be prepared by similar methods.
The molecular weight of these peptides obtained was determined by ESI-MS and the results of the partial peptide tests are shown in Table 2 below and FIGS. 1-5:
table 2 mass spectrometry determination of molecular weight results
| Numbering device | Sequence(s) | Molecular weight mass spectrometry analysis results |
| (4) | Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 | 829.60 |
| (9) | Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 | 902.62 |
| (13) | Palm-Lys-Val-Lys-Leu-Tyr-NH 2 | 886.66 |
| (14) | Palm-Lys-Val-Lys-Leu-Tyr-OH | 887.98 |
| (20) | Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 | 857.61 |
Example 7 cell proliferation assay
7.1 reagents and materials
Thiazole blue (MTT), dimethyl sulfoxide (DMSO), DMEM medium, fetal calf serum, and PBS.
7.2 instruments
Enzyme-labeled instrument, CO 2 Incubator, superclean bench.
7.3 cell lines
Human keratinocytes (HaCaT) were purchased from the kunming cell bank of the national academy of sciences typical culture collection committee.
7.4 sample to be tested
Polypeptide group: peptide (4), peptide (9), peptide (13) and peptide (20), the above samples were tested at concentrations of 6.25ppm, 12.5ppm, 25ppm.
Blank control group: PBS.
Positive control group: 2% DMSO.
7.5 Experimental methods
Taking cells in good exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, counting 1-4×10 5 Cell suspensions were prepared at each mL.
Inoculating cell suspension into 96-well plate at 200 μl/well, and standing at constant temperature with CO 2 Culturing in an incubator for 24 hours.
Changing liquid, adding polypeptide group, blank control group and positive control group sample, respectively, 20 μl/hole, placing at 37deg.C, 5% CO 2 Incubate in incubator for 72h.
mu.L of 5mg/mLMTT was added to each well and the mixture was continued at 37℃with 5% CO 2 Incubate in incubator for 4h. The original solution was discarded, 150. Mu.L/well of DMSO was added, and after shaking for 5min on a plate shaker, the OD value of each well was measured at a wavelength of 570nm using an ELISA reader, and the cell activity was calculated.
Cell activity = (test sample well OD-zeroed well OD)/(blank well OD-zeroed well OD) ×100%
7.6 experimental results
The MTT method is a method for detecting the survival and growth of cells, and the measured OD value is proportional to the activity of the cells. The higher the cell activity, the greater the value, whereas when the cell activity is significantly less than 80%, it is considered to have significant cytotoxicity.
The effect of the test sample on HaCaT cell activity is shown in fig. 6, and the result shows that compared with the blank control group, the positive control group has significantly reduced HaCaT cell activity, which indicates that 2% DMSO has toxic effect on HaCaT cells, while the polypeptide group has no obvious cytotoxicity, wherein the peptide (9) and the peptide (20) can significantly improve cell activity at low concentration, and promote proliferation of HaCaT keratinocyte.
From the results, the peptide of the invention can improve the activity of HaCaT keratinocytes and promote the proliferation of the HaCaT keratinocytes, thereby repairing the skin barrier and protecting the skin from external injury.
Example 8 photo aging test
8.1 reagents and materials
Fetal bovine serum, DMEM medium, PBS, penicillin, streptomycin, thiazole blue (MTT).
8.2 instruments
Enzyme-labeled instrument, CO 2 Incubator, superclean bench.
8.3 cell lines
Human keratinocytes (HaCaT) were purchased from the kunming cell bank of the national academy of sciences typical culture collection committee.
8.4 sample to be tested
Polypeptide group: the concentrations of the peptide (13) and the peptide (20) in the above samples were 6.25ppm and 12.5ppm.
Blank control group: PBS.
UV group: UV radiation, PBS was added.
8.5 Experimental methods
Taking cells in good exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, counting 1-4×10 5 Cell suspensions were prepared at each mL.
Properly diluting and taking 10000 cell suspensions per well to inoculate in a 96-well plateAnd (3) establishing a UV photoaging model when the cells grow to about 80%. The blank group was supplemented with 50 μl of PBS, medium was supplemented to 200 μl, and UV irradiation was not performed; adding appropriate amount of PBS, repeatedly washing to colorless, adding 50 μLPBS, and mixing at 80mJ/cm 2 And (3) irradiating under a UV lamp, wherein the distance between a lamp source and a culture bottle is 15cm, removing PBS after irradiation, adding a PBS solution and a culture medium to 200 mu L in a UV group, and adding a culture solution and a dilution sample to 200 mu L in a polypeptide group. The blank, UV, and polypeptide groups continued at 37deg.C, 5% CO 2 Incubate in incubator for 24h.
Thereafter 22. Mu.L of 5mg/mL MTT was added per well and the reaction was continued at 37℃with 5% CO 2 Incubate in incubator for 4h. The original solution was discarded, 150. Mu.L/well DMSO was added, and after shaking on a plate shaker for 5min, the reference OD values at 490nm and 630nm wavelengths were read using an ELISA reader.
8.6 experimental results
Skin aging is affected by endogenous and exogenous factors, such as genetics, environmental exposure, ultraviolet radiation, hormonal changes, and the like. The accumulation of these factors, particularly the irradiation of ultraviolet light, leads to alterations in the structure, function and appearance of the skin. The experiment selects 80mJ/cm 2 UV energy is radiated to build up a skin photoaging model.
The effect of the test sample on the activity of photo-aging cells is shown in fig. 7, and compared with the blank control group, the activity of the HaCaT cells of the UV group is obviously reduced after UV irradiation, which indicates that the photo-aging model is successfully established. Compared with the UV group, the polypeptide group can obviously improve the cell activity at low concentration, thereby improving the cell aging and generating obvious anti-photoaging effect.
Therefore, the peptide provided by the invention has excellent anti-photoaging effect and can be used for delaying aging.
Example 9 cell scratch assay
9.1 reagents and materials
Fetal bovine serum, DMEM medium, PBS, penicillin, streptomycin.
9.2 instruments
Optical microscope, CO 2 An incubator.
9.3 cell lines
Human keratinocytes (HaCaT) were purchased from the kunming cell bank of the national academy of sciences typical culture collection committee.
9.4 sample to be tested
Polypeptide group: peptide (13) and peptide (20), the above samples were tested at a concentration of 12.5ppm.
Blank control group: PBS.
Positive control group: EGF of 50U/mL.
9.5 Experimental methods
Taking one bottle of HaCaT cells in good exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, counting 1-4×10 5 Cell suspensions were prepared at each mL.
Cells were seeded at a density of 15 ten thousand cells per well in 24 well plates with 2mL of cell suspension per well, and after cell attachment was completed, cells were maintained in medium containing 0.5% -1% fetal bovine serum for 24h to synchronize them. Scratching with sterilized pipette tip, washing off dropped cells with PBS, adding sample to be tested, and continuing at 37deg.C and 5% CO 2 Incubation in incubator was performed for 24h, and the cells were observed under an optical microscope.
9.6 experimental results
The scratch migration test of the cells can reflect the proliferation repair capability of the cells. Scratch experiments were performed on the basis of HaCaT cell-filled dishes, and the effect of the test sample on cell proliferation and migration was evaluated by observing the migration of cells under an optical microscope 24h after the sample was applied.
The result of the cell scratch experiment is shown in fig. 8, and the result shows that the cell scratches of the blank control group are still obvious and the scratch interval is normal; the EGF positive control showed significant migration of cell proliferation compared to the blank, indicating successful modeling. The scratch distance of the polypeptide group is shortened compared with that of the cell scratch distance of the blank control group, and a cell migration track appears.
From these results, it is clear that the peptide of the present invention can promote cell proliferation and migration, and thus has skin-care effect.
EXAMPLE 10 determination of hyaluronic acid content
10.1 reagents and materials
Fetal bovine serum, DMEM medium, PBS, trypsin, hyaluronic acid detection kit, RIPA lysate, BCA protein kit.
10.2 instruments
Enzyme-labeled instrument, CO 2 Incubator, superclean bench, incubator.
10.3 cell lines
Human keratinocytes (HaCaT) were purchased from the kunming cell bank of the national academy of sciences typical culture collection committee.
10.4 sample to be tested
Polypeptide group: peptide (4), peptide (13) and peptide (20), all at a test concentration of 12.5ppm.
Blank control group: PBS.
10.5 Experimental methods
Taking one bottle of HaCaT cells in good exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, counting 1-4×10 6 Cell suspensions were prepared at each mL.
The cells were packed in 10 5 The cells/well were seeded on 6-well plates and the grouping was started until the cells were grown to about 80%. The blank group was supplemented with 200. Mu.LPBS and medium was supplemented to 800. Mu.L; 200. Mu.L of sample was added to the polypeptide group and medium was supplemented to 800. Mu.L. The blank group and the polypeptide group were placed at 37℃and 5% CO 2 Incubate in incubator for 48h.
After the completion of the culture, the cells were scraped off, 200. Mu.L of RIPA lysate was added to extract the protein, the mixture was frozen for 15 minutes, and the supernatant was centrifuged at 10000g for 10 minutes, and the total protein was measured by BCA method and quantified to 1mg/mL, and the operation was performed according to the instructions of the hyaluronic acid assay kit. The OD of each well was measured sequentially at 570nm with an ELISA reader over 15 min.
10.6 experimental results
Hyaluronic acid is one of main matrix components of human skin epidermis and also is an important component of skin barrier, and can lock moisture on skin surface, protect cells from pathogenic bacteria, accelerate recovery of skin tissue, improve physiological properties of skin, and has effects of natural moisturizing and skin repairing. The reduction or destruction of the hyaluronic acid content of the skin can cause the skin to lose moisture, and the epidermis to age, so that hyaluronic acid is also called an anti-aging factor. The experiment determines whether the peptide can improve the content of the hyaluronic acid by measuring the influence of the peptide on the content of the hyaluronic acid, so as to play a role in moisturizing and anti-aging repair.
The effect of the test sample on the content of hyaluronic acid is shown in fig. 9, and the result shows that the polypeptide groups can improve the content of hyaluronic acid to different degrees compared with the blank control groups, wherein the technical effects of the peptide (4) and the peptide (20) are better.
Therefore, the peptide disclosed by the invention can improve the content of hyaluronic acid, so that the skin barrier is enhanced, the moisture on the skin surface is supplemented, and the skin surface is moist and smooth, so that the peptide has the effects of moisturizing and resisting aging.
EXAMPLE 11 Silk fibroin expression experiments
11.1 reagents and materials
Fetal bovine serum, DMEM medium, PBS, filaggrin (FLG) detection kit.
11.2 instruments
Fluorescence microscope, CO 2 Incubator, superclean bench, incubator.
11.3 cell lines
Human keratinocytes (HaCaT) were purchased from the kunming cell bank of the national academy of sciences typical culture collection committee.
11.4 sample to be tested
Polypeptide group: peptide (4), peptide (9), peptide (13) and peptide (20), the above samples were tested at concentrations of 10ppm and 50ppm.
Blank control group: PBS.
UV group: UV radiation, PBS was added.
11.5 Experimental methods
Frozen HaCaT cells were taken and cultured according to 1: and (5) carrying out passage 2 to about 5 generations, and selecting cells with better growth vigor as experimental objects. Taking cell suspension according to 10 4 Inoculating the cells/wells onto 96-well plate, adding complete culture medium, standing at 37deg.C and 5% CO 2 IncubatorAnd (3) culturing for 24 hours, and establishing a UV photoaging model when the cells grow to be about 80 percent.
The original medium solution was aspirated with a vacuum pump and the grouping was started. The blank control group was supplemented with 200 μLPBS, medium was supplemented to 1200 μL, and UV irradiation was not performed; adding appropriate amount of PBS, repeatedly washing to colorless, adding 200 μLPBS, and mixing at 80mJ/cm 2 And (3) irradiating under a UV lamp, wherein the distance between a lamp source and a culture bottle is 15cm, removing PBS after irradiation, adding a PBS solution and a culture medium to 1200 mu L in a UV group, and adding a culture solution and diluting a sample to 1200 mu L in a multiple manner in a polypeptide group. The blank, UV, and polypeptide groups continued at 37deg.C, 5% CO 2 Incubate in incubator for 24h.
After incubation, cells were digested, climbing up the slide for 12h, and after staining the cells with a Filaggrin (FLG) detection kit, they were observed under a fluorescence microscope.
11.6 experimental results
Filaggrin (FLG) is an important molecule for connecting keratin fibers in the stratum corneum of human skin, and can prevent loss of epidermis moisture and invasion of foreign substances, so that the expression of FLG can be improved to enhance or repair skin barrier. The experiment selects 80mJ/cm 2 UV energy is radiated to build a skin stratum corneum cell model, and the influence of a sample on FLG expression is detected, so that whether the peptide disclosed by the invention can promote FLG expression is analyzed.
The effect of the test sample on FLG expression is shown in fig. 10, which shows that the FLG content of the UV group is significantly reduced (as shown in the light-colored part of fig. 10) after UV irradiation compared with the blank group, indicating that the experimental cell model was successfully established. Compared with the UV group, the polypeptide group can improve the content of FLG to different degrees within the range of 10-50ppm, promote the expression of FLG, and has excellent effect of promoting the expression of FLG. Among them, the peptide (13) has the best technical effect.
From this, it is clear that the peptides of the present invention are capable of promoting FLG expression, enhancing or repairing skin barrier.
EXAMPLE 12 hyaluronidase inhibition assay
12.1 laboratory apparatus and reagents
Spectrophotometry, phosphate Buffered Saline (PBS), hyaluronic acid, hyaluronidase.
12.2 sample to be tested
The concentrations of the peptides (13) and (14) were 50ppm and 100ppm.
12.3 Experimental methods
The experiments were divided into four groups: the total reaction volumes of the control group A1 (pbs+hyaluronidase), the enzyme-free control group A2 (pbs+hyaluronidase-free solvent), the sample group B1 (sample to be tested+hyaluronidase), and the enzyme-free sample group B2 (sample to be tested+hyaluronidase-free solvent) were the same.
100. Mu.L CaCl was grouped into groups 2 (2.5 mmol/L) and 500. Mu.L of hyaluronidase (500U/mL) or solvent without hyaluronidase are mixed, and 20. Mu.L is taken and placed in a constant temperature gas bath at 37 ℃ for shaking for 20min; adding 20 mu LPBS into the blank control group, and placing the blank control group into a constant temperature air bath at 37 ℃ to oscillate for 20min; adding 20 mu L of samples with different concentrations into the sample group, and placing the samples in a constant-temperature air bath at 37 ℃ for shaking for 20min; adding 40 μl of hyaluronic acid, standing at 37deg.C, and oscillating for 40min in constant temperature gas bath; adding 10 mu L of acetylacetone solution, placing in a constant temperature air bath at 50 ℃ for shaking for 10min, a baking oven at 75 ℃ for 40min, and a baking oven at 50 ℃ for 10min, rapidly tearing off the preservative film after the reaction is finished and cooled to avoid generating water vapor, adding 100 mu L of 96% absolute ethyl alcohol and 10 mu L of Ehrlich reagent, and measuring the light absorption value at 492 nm.
12.4 experimental results
Hyaluronidase can decompose hyaluronic acid in vivo to become low molecular weight acidic stimulus, thereby inducing histamine release and inducing body to produce sensitive symptoms. In addition, the reduction of hyaluronic acid can disrupt the barrier function of the skin, resulting in loss of moisture from the interior of the skin. Therefore, the effect of relieving, moisturizing and repairing the skin barrier can be achieved by inhibiting the activity of hyaluronidase.
The effect of the test sample on the hyaluronidase inhibition is shown in FIG. 11. The results show that both peptide (13) and peptide (14) are capable of inhibiting hyaluronidase activity at the tested concentrations. The inhibition rate of the peptide (13) at 100ppm was 49.40%, and the inhibition rate of the peptide (14) at 100ppm was 40.96%.
The peptide (13) is different from the peptide (14) in that the C-terminal of the peptide chain of the former is amidated (-NH) 2 ) The latter peptide chain being in the form of-OH at the C-terminus. Experiments have shown that the peptides of the invention, whether the C-terminal of the peptide chain is-NH 2 And the-OH has the same efficacy, can inhibit the activity of hyaluronidase, and plays roles of relieving, moisturizing and repairing skin barriers.
In conclusion, the peptide of the invention can improve cell activity, promote cell proliferation and migration, strengthen or repair skin barrier, and has anti-aging repair effect; also has anti-aging or photoaging effects; also has effects of relieving and keeping moisture.
EXAMPLE 13 preparation of liposomes containing peptide (4)
The preparation method comprises the following steps: dipalmitoyl phosphatidylcholine was weighed and dissolved in chloroform. Evaporating the solvent under vacuum until a thin layer of phospholipid is obtained, and hydrating the layer by treating it with an aqueous peptide solution of the desired concentration at 55℃to obtain a multilamellar liposome. The multi-chamber liposome is subjected to high-pressure homogenization treatment to obtain single-chamber liposome with smaller and uniform size.
EXAMPLE 14 preparation of peptide (9) -containing essence
The preparation method comprises the following steps: stirring and heating the purified water to 85 ℃, and preserving heat for 30min; pre-dissolving sodium hyaluronate and xanthan gum in butanediol, adding into water, stirring and dissolving completely; stirring and cooling to 35 ℃, adding the rest ingredients, and stirring uniformly.
EXAMPLE 15 preparation of emulsion containing peptide (13)
The preparation method comprises the following steps: dissolving the peptide (13) with water to obtain a polypeptide solution; heating cetostearyl alcohol (and) cetylglucosides, jojoba oil, mineral oil, isopropyl palmitate to 85deg.C, and stirring well; obtaining phase A; dissolving glycerol, allantoin, polyacrylamide (and) C13-14 isoparaffin (and) laureth-7 with water, and heating to 85deg.C to obtain phase B; adding phase A into phase B rapidly, homogenizing at constant temperature for 3-5min, and cooling; cooling to below 60deg.C, adding antiseptic, stirring, cooling to below 45deg.C, and adding polypeptide solution and essence.
EXAMPLE 16 microemulsion composition containing peptide (14)
The preparation method comprises the following steps: weighing the component of phase B according to the dosage of the prescription, and adding the component into a container. Then, phase D was added to phase B and homogenized with continuous stirring. Phase a was then added to the mixture. And finally, adding the phase C and stirring uniformly to obtain the composite material.
EXAMPLE 17 preparation of toner containing peptide (20)
The preparation method comprises the following steps: dissolving allantoin and glycerol with water, heating to 85deg.C, and maintaining for 30 min; dissolving PEG-7 glycerol cocoate and peptide (20) with water; the above solutions are cooled and then mixed, and the mixed solution is obtained after uniform stirring; and sequentially adding propylene glycol, preservative and essence into the mixed solution, adding water and stirring uniformly to obtain the product.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiment and all such alterations and modifications as fall within the scope of the embodiments of the invention.
Finally, it is further noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article or terminal device comprising the element.
The novel peptides, compositions and uses of the invention have been described in detail, with specific examples being employed herein to illustrate the principles and embodiments of the invention, the above examples being provided only to assist in understanding the methods of the invention and the core ideas thereof; meanwhile, as those skilled in the art will have variations in the specific embodiments and application scope in accordance with the ideas of the present invention, the present description should not be construed as limiting the present invention in view of the above.
Claims (12)
1. A peptide represented by the formula (I), or a stereoisomer thereof, or a mixture of its stereoisomers, or a salt thereof,
R 1 -X 1 -X 2 -X 3 -Leu-Tyr-X 4 -X 5 -R 2 (I)
in the formula (I) of the present invention,
X 1 selected from: -Gly-, -Lys-or a bond;
X 2 selected from: -Nle-, -Val-, -Leu-, or-Ile-;
X 3 selected from: -Lys-, -Arg-or-His-;
X 4 selected from: -Gly-or a bond;
X 5 selected from: -Ser-or bond;
R 1 selected from: h or R 3 -CO-, wherein R 3 Selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
R 2 selected from: -NR 4 R 5 OR-OR 4 Wherein each R is 4 And R is 5 Independently of each other selected from: H. substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
alkyl refers to a saturated aliphatic linear or branched alkyl group having 1 to 24 carbon atoms (optionally having 1 to 16 carbon atoms; optionally having 1 to 14 carbon atoms; optionally having 1 to 12 carbon atoms; optionally having 1, 2, 3, 4, 5, or 6 carbon atoms); optionally selected from: methyl, ethyl, isopropyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 2-ethylhexyl, 2-methylbutyl, or 5-methylhexyl;
The alkenyl group refers to a straight or branched alkenyl group having 2 to 24 carbon atoms (optionally having 2 to 16 carbon atoms; optionally having 2 to 14 carbon atoms; optionally having 2 to 12 carbon atoms; optionally having 2, 3, 4, 5, or 6 carbon atoms); the alkenyl group has one or more carbon-carbon double bonds, optionally 1, 2 or 3 conjugated or non-conjugated carbon-carbon double bonds; the alkenyl group is bound to the remainder of the molecule by a single bond; optionally selected from: vinyl, oleyl, or linoleyl;
optionally, the substituents in the "substituted alkyl", "substituted alkenyl" are selected from C 1 -C 4 An alkyl group; a hydroxyl group; c (C) 1 -C 4 An alkoxy group; an amino group; c (C) 1 -C 4 An aminoalkyl group; c (C) 1 -C 4 A carbonyloxy group; c (C) 1 -C 4 An oxycarbonyl group; halogen (e.g. fluorine, chlorine, bromine)And iodine); cyano group; a nitro group; an azide; c (C) 1 -C 4 An alkylsulfonyl group; a mercaptan; c (C) 1 -C 4 Alkylthio; c (C) 6 -C 30 Aryloxy groups such as phenoxy; -NR b (C＝NR b )NR b R c Wherein R is b And R is c Is independently selected from: H. c (C) 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 18 Aryl, C 7 -C 17 Aralkyl groups, heterocyclic groups having three to ten members, or protecting groups for amino groups.
2. The peptide of formula (I), or a stereoisomer thereof, or a mixture of its stereoisomers, or a salt thereof, as claimed in claim 1, wherein R 1 Selected from: H. acetyl, t-butyryl, hexanoyl, 2-methylhexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl or linoleoyl; r is R 4 、R 5 Independently of each other selected from: H. methyl, ethyl, hexyl, dodecyl or hexadecyl;
alternatively, R 1 Selected from H, acetyl, lauroyl, myristoyl or palmitoyl; r is R 4 Is H and R 5 Selected from: H. methyl, ethyl, hexyl, dodecyl or hexadecyl;
alternatively, R 1 Is H, acetyl or palmitoyl; r is R 2 is-OH or-NH 2 。
3. The peptide of formula (I), or a stereoisomer thereof, or a mixture of its stereoisomers, or a salt thereof, according to claim 1, wherein the peptide is selected from the group consisting of the following peptides (1) to (40):
(1)H-Gly-Nle-Lys-Leu-Tyr-OH；
(2)Ac-Gly-Nle-Lys-Leu-Tyr-NH 2 ；
(3)Palm-Gly-Nle-Lys-Leu-Tyr-OH；
(4)Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 ；(5)H-Val-Lys-Leu-Tyr-Gly-Ser-OH；
(6)H-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；(7)Ac-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；(8)Palm-Val-Lys-Leu-Tyr-Gly-Ser-OH；(9)Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；(10)H-Lys-Val-Lys-Leu-Tyr-OH；
(11)H-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(12)Ac-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(13)Palm-Lys-Val-Lys-Leu-Tyr-NH 2 ；(14)Palm-Lys-Val-Lys-Leu-Tyr-OH；(15)H-Gly-Nle-Arg-Leu-Tyr-OH；
(16)H-Gly-Nle-Arg-Leu-Tyr-NH 2 ；
(17)Ac-Gly-Nle-Arg-Leu-Tyr-OH；
(18)Ac-Gly-Nle-Arg-Leu-Tyr-NH 2 ；
(19)Palm-Gly-Nle-Arg-Leu-Tyr-OH；(20)Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 ；(21)H-Lys-Leu-Lys-Leu-Tyr-OH；
(22)Ac-Lys-Leu-Lys-Leu-Tyr-NH 2 ；
(23)Ac-Gly-Ile-Lys-Leu-Tyr-NH 2 ；
(24)H-Gly-Leu-Arg-Leu-Tyr-Ser-OH；(25)H-Gly-Val-Lys-Leu-Tyr-NH 2 ；
(26)Palm-Gly-Val-His-Leu-Tyr-NH 2 ；(27)Ac-Gly-Nle-Arg-Leu-Tyr-Gly-OH；(28)H-Nle-Lys-Leu-Tyr-Gly-OH；
(29)Ac-Ile-Lys-Leu-Tyr-Gly-Ser-NH 2 ；(30)H-Lys-Nle-Arg-Leu-Tyr-OH；
(31)H-Ile-Lys-Leu-Tyr-Ser-NH 2 ；
(32)Ac-Gly-Nle-Lys-Leu-Tyr-OH；
(33)Palm-Gly-Leu-Lys-Leu-Tyr-NH 2 ；
(34)H-Gly-Leu-Lys-Leu-Tyr-Gly-OH；
(35)Ac-Ile-Lys-Leu-Tyr-Gly-NH 2 ；
(36)H-Ile-Arg-Leu-Tyr-Gly-Ser-OH；
(37)H-Val-His-Leu-Tyr-Gly-NH 2 ；
(38)Ac-Val-His-Leu-Tyr-Gly-Ser-OH；
(39)Palm-Gly-Leu-Arg-Leu-Tyr-Gly-NH 2 ；
(40)H-Gly-Leu-Arg-Leu-Tyr-Ser-OH。
4. the peptide of formula (I) or a stereoisomer thereof, or a mixture of its stereoisomers, or a salt thereof, according to claim 3, wherein the peptide is selected from the group consisting of peptide (3), peptide (4), peptide (8), peptide (9), peptide (13), peptide (14), peptide (19) and peptide (20), specifically,
(3)Palm-Gly-Nle-Lys-Leu-Tyr-OH；
(4)Palm-Gly-Nle-Lys-Leu-Tyr-NH 2 ；
(8)Palm-Val-Lys-Leu-Tyr-Gly-Ser-OH；
(9)Palm-Val-Lys-Leu-Tyr-Gly-Ser-NH 2 ；
(13)Palm-Lys-Val-Lys-Leu-Tyr-NH 2 ；
(14)Palm-Lys-Val-Lys-Leu-Tyr-OH；
(19)Palm-Gly-Nle-Arg-Leu-Tyr-OH；
(20)Palm-Gly-Nle-Arg-Leu-Tyr-NH 2 。
5. the peptide of formula (I) according to any one of claim 1 to 4, wherein the peptide is a stereoisomer thereof or a mixture of stereoisomers thereof or a salt thereof,
The salts include metal salts of peptides of formula (I), wherein the metal comprises: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum;
alternatively, the salt includes a salt of a peptide of formula (I) with an organic base comprising: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine;
alternatively, the salt includes a salt of a peptide represented by formula (I) with an inorganic acid or an organic acid, wherein the organic acid includes: acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoic acid or gluconic acid; the inorganic acid includes: hydrochloric acid, sulfuric acid, boric acid or carbonic acid.
6. A composition comprising an effective amount of a peptide of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, as defined in any one of claims 1 to 5, together with at least one excipient and optionally an adjuvant;
optionally, the adjuvant is selected from: other agents that activate S1PR2 activity, analgesics, agents that inhibit PAR-2 activity, collagen synthesis stimulators, agents that modulate PGC-1 alpha synthesis, agents that modulate PPARgamma activity, agents that increase or decrease triglyceride levels in adipocytes, agents that stimulate or retard adipocyte differentiation, lipolytic or lipolysis-stimulating agents, lipolytic agents, adipogenic agents, inhibitors of acetylcholine receptor aggregation, agents that inhibit muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloproteinase inhibitors, melanin synthesis stimulators or inhibitors, whitening or decolouring agents, pro-pigmentation agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5 alpha-reductase inhibitors, inhibitors of lysyl hydroxylase and/or prolyl hydroxylase, antioxidants, free radical scavengers and/or agents that combat atmospheric pollution active carbonyl species scavengers, anti-glycation agents, antihistamines, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioning agents, moisture retaining materials, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermohydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gelling polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating the lower eye pocket, keratolytic agents, antimicrobial agents, antifungal agents, bactericides, bacteriostats, agents capable of stimulating the synthesis of dermis or epidermis macromolecules and/or inhibiting or preventing their degradation, agents that stimulate elastin synthesis, agents that stimulate decorin synthesis, agents that stimulate laminin synthesis, an agent that stimulates defensin synthesis, an agent that stimulates chaperonin synthesis, an agent that stimulates cAMP synthesis, an agent that stimulates HSP70 synthesis, an agent that stimulates heat shock protein synthesis, an agent that stimulates hyaluronic acid synthesis, an agent that stimulates fibronectin synthesis, an agent that stimulates deacetylase synthesis, an agent that stimulates synthesis of lipids and stratum corneum components, ceramides, fatty acids, an agent that inhibits collagen degradation, an agent that inhibits elastin degradation, an agent that inhibits serine proteases, an agent that stimulates fibroblast proliferation, an agent that stimulates keratinocyte proliferation, an agent that stimulates adipocyte proliferation, an agent that stimulates melanocyte proliferation, an agent that stimulates keratinocyte differentiation, an agent that inhibits acetylcholinesterase, a skin relaxant, an agent that stimulates glycosaminoglycan synthesis, an anti-hyperkeratosis agent, an acne lytic agent, an anti-psoriasis agent, an anti-rash agent DNA repair agents, DNA protectants, stabilizers, antipruritics, agents for treating and/or caring for sensitive skin, solidifying agents, tightening agents, restructuring agents, stretch-proofing agents, agents that regulate sebum production, antiperspirant agents, agents that stimulate healing, agents that assist healing, agents that stimulate re-epithelialization, agents that assist re-epithelialization, cytokines, sedatives, anti-inflammatory agents, anesthetics, agents that act on capillary circulation and/or microcirculation, agents that stimulate angiogenesis, agents that inhibit vascular permeability, venous tension agents, agents that act on cellular metabolism, agents that act on improving dermal-epidermal junction, agents that induce hair growth, hair growth inhibition or delay agents, fragrances, chelating agents, plant extracts, essential oils, marine extracts, agents from biofermentation processes, inorganic salts, cell extracts, sunscreens, agents that act on cellular metabolism, and organic or inorganic photoprotective agents effective against A and/or B ultraviolet light, or mixtures thereof.
7. The composition of claim 6, wherein the formulation of the composition is selected from the group consisting of: cream, oil, balm, foam, lotion, gel, wipe, slurry, ointment, mousse, powder, stick, pen, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, elixir, polysaccharide film, jelly, or gelatin.
8. A delivery system or sustained release system comprising an effective amount of a peptide of formula (I) as defined in any one of claims 1 to 5, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition as defined in claim 6 or 7;
the delivery system or slow release system is selected from: liposomes, oleosomes, nonionic surfactant liposome vesicles, ethosomes, millimeter capsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, lipid vesicles, micelles, millimeter spheres, microspheres, nanospheres, lipid spheres, microemulsions, nanoemulsions, millimeter particles, microparticles or nanoparticles.
9. Use of a peptide of formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition according to claim 6 or 7, or a delivery system or a slow release system according to claim 8, for the preparation of a composition for anti-ageing or photoaging.
10. Use of a peptide of formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition according to claim 6 or 7, or a delivery system or a slow release system according to claim 8, for the preparation of a composition for anti-ageing repair comprising one or more of increasing cell activity, promoting cell proliferation and migration, enhancing or repairing skin barrier.
11. Use of a peptide of formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition according to claim 6 or 7, or a delivery system or a slow release system according to claim 8, for the preparation of a composition for relief.
12. Use of a peptide of formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or a composition according to claim 6 or 7, or a delivery system or a slow release system according to claim 8, for the preparation of a composition for moisturizing.
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| CN202311304139.0A CN117327150A (en) | 2023-04-20 | 2023-04-20 | Peptides, compositions and uses thereof |
| CN202310428893.9A CN116284241B (en) | 2023-04-20 | 2023-04-20 | Peptides, compositions and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117126242A (en) * | 2023-10-25 | 2023-11-28 | 深圳市维琪科技股份有限公司 | Heptapeptides, compositions and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117357426A (en) * | 2023-12-07 | 2024-01-09 | 深圳市维琪科技股份有限公司 | Novel use of pentapeptides |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6358921B1 (en) * | 1996-10-11 | 2002-03-19 | Pence, Inc. | Antimicrobial peptide compositions and method |
| CN114315960A (en) * | 2021-12-31 | 2022-04-12 | 深圳市维琪医药研发有限公司 | Modified peptide, and cosmetic composition or medicinal composition and application thereof |
| CN115583988A (en) * | 2022-10-14 | 2023-01-10 | 深圳市维琪医药研发有限公司 | Synthetic peptides, cosmetic or pharmaceutical compositions and uses thereof |
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| CN113896768B (en) * | 2021-11-01 | 2022-10-14 | 深圳市维琪医药研发有限公司 | Antibacterial peptides and their cosmetic or pharmaceutical compositions and uses |
| CN115594735B (en) * | 2022-11-25 | 2023-09-22 | 深圳市维琪科技股份有限公司 | Peptides with anti-aging effect, compositions and uses thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358921B1 (en) * | 1996-10-11 | 2002-03-19 | Pence, Inc. | Antimicrobial peptide compositions and method |
| CN114315960A (en) * | 2021-12-31 | 2022-04-12 | 深圳市维琪医药研发有限公司 | Modified peptide, and cosmetic composition or medicinal composition and application thereof |
| CN115583988A (en) * | 2022-10-14 | 2023-01-10 | 深圳市维琪医药研发有限公司 | Synthetic peptides, cosmetic or pharmaceutical compositions and uses thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117126242A (en) * | 2023-10-25 | 2023-11-28 | 深圳市维琪科技股份有限公司 | Heptapeptides, compositions and uses thereof |
| CN117126242B (en) * | 2023-10-25 | 2024-02-13 | 深圳市维琪科技股份有限公司 | Heptapeptides, compositions and uses thereof |
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| CN116284241B (en) | 2023-10-31 |
| CN117327150A (en) | 2024-01-02 |
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